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Delineating Hypoxic Regulation of Metabolic Pathways to Promote Stem Cell Function

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Review of “Novel pathway for hypoxia-Induced proliferation and migration in human mesenchymal stem cells: Involvement of HIF-1α, FASN, and mTORC1” from Stem Cells by Stuart P. Atkinson

The modulation of stem cell fate and function via oxygen and metabolic signaling is a complex field of research which may provide us with means to control stem cell maintenance and differentiation. Low oxygen levels (hypoxia) characterize many stem cell niches and this can alter nutrient metabolism-associated gene expression patterns [1, 2] via hypoxia-inducible factor-1 alpha (HIF-1α). Furthermore, lipid metabolism and energy production is also an important modulator of stem cell maintenance through the functions of enzymes such as fatty acid synthase (FASN) [3, 4]. Now, researchers from the laboratory of Ho Jae Han (Seoul National University, South Korea), have studied oxygen/metabolic signaling in umbilical cord blood (UCB)-derived hMSCs (UCB-hMSCs), and their findings may increase the clinical potential of such cell types by the improving upon current methods to sustain, develop, and control UCB-hMSCs [5].

Initial studies by the group found an increase in both the proliferation and migratory capacity of UCB-hMSCs after 24 hours of hypoxia. This response correlated to an upregulation of lipid metabolism associate gene expression (FASN, stearoyl-CoA desaturase 1 (SCD1) and SCD5) and an increase in the production of fatty acids (FAs), perhaps providing cells under hypoxia with an alternative energy source. Interestingly, chemical inhibition of FASN (via cerulenin treatment) inhibited FA production and the pro-proliferative and pro-migratory effects of hypoxia on UCB-hMSCs in vitro, while the supplementation of cells with FAs (palmitic acid) counteracted the effects of cerulenin and facilitated the enhanced proliferation and migration seen under hypoxia. The group then confirmed their in vitro studies in vivo showing that FASN inhibition diminished the ability of UCB-hMSCs to migrate into and heal a mouse skin wound in a healing assay (see figure).

Subsequent detailed gene expression analysis found that HIF-1α, HIF-2α, sterol regulatory element binding protein 1 (SREBP1), and SREBP1 cleavage activating protein (SCAP) all increased upon hypoxic treatment of UCB-hMSCs. Importantly, silencing of the HIF-1α gene using short hairpin RNA inhibited the hypoxia-mediated upregulation of SCAP, SREBP1, and FASN expression, while the addition of an inhibitor of SCAP-SREBP1 interaction (fatostatin), repressed hypoxia-induced SREBP1 maturation and FASN expression.

Hypoxia also induced the phosphorylation of mammalian target of rapamycin (mTOR), a nutrient sensing molecule, in UCB-hMSCs. FASN inhibition inhibited this phosphorylation event, while FA addition was able to counteract FASN inhibition and promote mTOR phosphorylation. Further in depth studies also demonstrated that hypoxia-induced FASN expression is an upstream regulator of mTOR Complex 1 (mTORC1) activation. The group next found higher levels of cycle regulatory proteins, which mediate higher proliferation, in addition to proteins associated with enhanced migratory capacity under hypoxic conditions in UCB-hMSCs, and inhibition of mTOR by rapamycin led to a reduction in the expression of these proteins and therefore reduced proliferative and migratory abilities.

This detailed study describes for the first time that HIF-1α/FASN/mTORC1 interactions promote UCB-hMSC proliferation and migration through hypoxia-induced increases in lipid metabolism. Interestingly, the addition of FAs to UCB-hMSCs induced a hypoxia-like response and therefore may be employed to “prime” such stem cells prior to transplantation in order to increase any therapeutic effects [6]. Indeed, hematopoietic stem cells (HSCs) also function better under hypoxic conditions [7], and so mimicking hypoxia in vitro through FA addition may promote in vivo-like functionality in many stem cell populations which exist in a hypoxic niche.

References

  1. Rey S, Luo W, Shimoda LA, et al. Metabolic reprogramming by HIF-1 promotes the survival of bone marrow-derived angiogenic cells in ischemic tissue. Blood 2011;117:4988-4998.
  2. Krishnamurthy P, Ross DD, Nakanishi T, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. The Journal of biological chemistry 2004;279:24218-24225.
  3. Menendez JA and Lupu R Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007;7:763-777.
  4. Kuhajda FP, Jenner K, Wood FD, et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proceedings of the National Academy of Sciences of the United States of America 1994;91:6379-6383.
  5. Lee HJ, Ryu JM, Jung YH, et al. Novel Pathway for Hypoxia-Induced Proliferation and Migration in Human Mesenchymal Stem Cells: Involvement of HIF-1alpha, FASN, and mTORC1. Stem Cells 2015;33:2182-2195.
  6. Kang JX, Wan JB, and He C Concise review: Regulation of stem cell proliferation and differentiation by essential fatty acids and their metabolites. Stem Cells 2014;32:1092-1098.
  7. Mantel CR, O'Leary HA, Chitteti BR, et al. Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell 2015;161:1553-1565.